Infusion Of Vasoactive Intestinal Polypeptide Research Articles

Action and localization of vasoactive intestinal peptide in the coronary circulation: Evidence for nonadrenergic, noncholinergic coronary regulation

Vasoactive intestinal polypeptide, a neurotransmitter peptide detected in animal and human hearts, has been found in nerves of coronary arteries. To determine the amount and distribution of vasoactive intestinal polypeptide in the large coronary vessels and its possible participation in coronary vasoregulation, two groups of animals were studied. In the first group, 11 anesthetized dogs were sacrificed to collect three (1 cm) segments along the circumflex and left anterior descending coronary arteries. These segments represented proximal (I), middle (II) and distal (III) portions of the two arteries. Concentrations (ng/g) of vasoactive intestinal polypeptide-like immunoreactive substance were determined by radioimmunoassay. Vasoactive intestinal polypeptide-like immunoreactivity was present in the left anterior descending (I = 7.28 +/- 1.65, II = 3.74 +/- 0.57, III = 2.29 +/- 0.53) and circumflex (I = 4.16 +/- 1.52, II = 4.58 +/- 1.13, III = 4.00 +/- 0.81) coronary arteries. The difference in vasoactive intestinal polypeptide-like immunoreactivity among epicardial segments of the anterior descending artery was significant, but there was no significant difference among segments of the circumflex coronary artery. In the second group (eight closed chest anesthetized dogs), the effects of vasoactive intestinal polypeptide intracoronary infusion on epicardial coronary constriction were examined at rest and with the artery constricted by serotonin. Left anterior descending (segments I, II and III) artery responses (% area change) to vasoactive intestinal polypeptide and vasoactive intestinal polypeptide plus serotonin were examined using quantitative coronary angiography. Vasoactive intestinal polypeptide infusion resulted in significant vasodilation in all the segments (I, II and III) of the left anterior descending artery.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasoactive intestinal polypeptide effects a central inhibition of pulsatile luteinizing hormone secretion in ovariectomized rats.

Recent studies implicate vasoactive intestinal polypeptide (VIP) as a neurotransmitter or neuromodulator, and several observations suggest that VIP, originating within the brain, may alter the secretion of GnRH. We have tested the hypothesis that VIP acts as a central nervous system regulator of pulsatile GnRH secretion, as reflected in pulsatile LH release, by assessing the effect of intraventricularly administered VIP on several parameters of LH secretion in ovariectomized (OVX) rats. To examine the possibility that centrally administered VIP alters pituitary responsiveness to GnRH, we challenged OVX rats with GnRH and compared the LH response in VIP-treated animals with that in control animals. Finally, we tested the hypothesis that exposure of the animal to gonadal steroids alters VIP's effect on LH secretion by assessing LH release during central administration of VIP in OVX rats pretreated with estrogen and progesterone. Unanesthetized rats with external jugular cannulae were bled at 5-min intervals for 2 h before infusion and for 2 h during continuous intraventricular infusion of either VIP (1.8 nmol/h) or saline. Blood samples (300 or 400 microliter) were replaced with an equal volume of a blood replacement mixture. VIP infusion significantly reduced LH pulse frequency by 80% (P less than 0.002) and mean LH levels by 60% (P less than 0.002), but did not significantly affect LH pulse amplitude. In contrast, saline infusion produced no significant change in any of these parameters. The plasma LH response to 2 ng GnRH, iv, in VIP-treated animals did not differ significantly from that in control animals. Finally, VIP infusion had no discernible effect on LH secretion in OVX rats pretreated with estradiol benzoate (50 micrograms) and progesterone (25 mg). These results demonstrate that VIP can profoundly inhibit pulsatile LH secretion in the OVX rat and provide evidence to suggest that this effect is not due to diminished pituitary responsiveness to GnRH. Based upon these observations, we argue that VIP, originating within the brain, may be an important inhibitory regulator of pulsatile GnRH secretion.

Adrenergic effects on secretion of epidermal growth factor from Brunner's glands.

The influence of the sympathetic nervous system and adrenergic agonists on flow rate and secretion of epidermal growth factor (EGF) from Brunner's glands has been investigated in the rat. Chemical sympathectomy by administration of 6-hydroxydopamine increased volume secretion and output of EGF from Brunner's glands but depleted the glands of EGF. Infusion of noradrenaline, an alpha-adrenergic agonist, inhibited basal and vasoactive intestinal polypeptide (VIP) stimulated flow rate and output of EGF from Brunner's glands and increased the amount of EGF in the tissue. Vasoactive intestinal polypeptide also increased the amount of EGF in Brunner's gland tissue and this was unchanged after simultaneous infusion of VIP and noradrenaline as well as VIP and isoproterenol, a beta-adrenergic agonist. Isoproterenol had no effect on basal and VIP stimulated secretion of EGF from Brunner's glands. The presence of PAS-positive mucus in Brunner's glands was unchanged during infusion of noradrenaline whereas VIP induced a depletion of Brunner's gland mucus which in turn was prevented by simultaneous infusion of noradrenaline. This study indicates that the sympathetic nervous system influence the volume secretion, output of EGF and mucus content in Brunner's glands probably by activation of alpha-adrenergic pathways.

Effect of regulatory polypeptides on the substance P stimulated lower esophageal sphincter pressure in pigs

The effect of graded doses of vasoactive intestinal polypeptide (VIP), enkephalin, neuropeptide Y (NPY), gastrin-17, pentagastrin, cholecystokinin (CCK)-4, CCK-8, neurotensin, somatostatin, and thyrotropin-releasing hormone (TRH) on the substance P (SP)-stimulated lower esophageal sphincter pressure (LESP) in anaesthetized pigs was studied by direct infusion of the peptides into the arterial supply of the lower esophageal sphincter (LES). Infusion of SP in a dose of 20 pmol/kg per min for 3 min significantly increased the LESP ( P < 0.01). Simultaneous VIP infusion at 5–40 pmol/kg per min showed a dose-dependent inhibition of the effect of SP on the LESP. None of the other peptides had any effect on the LESP during simultaneous infusion of SP. Pharmacological blockade by atropine (250 μ/kg) or guanethidine (1 mg/kg) had no effect on the SP-stimulated LESP. In conclusion, the SP-induced stimulation of the LESP is abolished by VIP, and both peptides seem to play a role in the complex regulation of the LESP.

Vasoactive intestinal polypeptide stimulates nonovarian progesterone secretion in rabbits

Recent experiments conducted in this laboratory have shown that intravenous infusions of vasoactive intestinal polypeptide (VIP) induce significant increases in plasma progesterone (P) in female rabbits. The purpose of this study was to determine the organ source of this P and to clarify the mechanisms by which it is induced. Intravenous infusions of VIP (37.5, 75, and 150 pmol/kg per min for 60 min) produced acute dose-dependent increases in plasma P in intact estrous rabbits. In ovariectomized (OVX) animals, VIP infusion (75 pmol/kg per min) produced a P increase of the same magnitude. In animals both OVX and adrenalectomized (ADX), this VIP effect was eliminated. The only significant change noted in luteotropic hormone (LH) or follicle stimulating hormone (FSH) was a decrease in FSH immediately following VIP infusion (150 pmol/kg). VIP infusion significantly increased plasma cortisol in intact and OVX animals, but not in OVX/ADX animals. It is concluded that VIP primarily stimulates the adrenal component of P secretion in the rabbit, via mechanisms independent of LH or FSH.

Vasoactive intestinal polypeptide, cholecystokinin, glucagon, and bile-oleate-induced jejunal hyperemia.

The purpose of this study was to evaluate the roles of vasoactive intestinal polypeptide (VIP), cholecystokinin (CCK), and glucagon in the local regulation of the lipid-induced intestinal hyperemia. Total blood flow and the arteriovenous hormone concentration gradient were measured in isolated jejunal loops of anesthetized dogs with either saline, bile (10% in normal saline), oleic acid (40 mM in normal saline), or oleic acid and bile in the lumen. The bile-oleic acid mixture increased both blood flow (+21 +/- 7%) and VIP release (+118 +/- 7%), while CCK release was considerably less. There was a transient rise in glucagonlike immunoreactivity but no change in pancreatic glucagon release. Neither bile nor oleic acid alone altered either local blood flow or hormone release. Infusion of VIP into the arterial circulation of the jejunum significantly reduced vascular resistance (-11 +/- 4%) but at a dose (150 ng . min-1 X 100 g-1) 10 times that released in response to the bile-oleic acid mixture. This study indicates that oleic acid increases both blood flow and intestinal hormone production only when present in the lumen in micellar form and suggests that VIP could play a role in the jejunal vascular response to fat.

Plasma concentration of prolactin during four-day osmotic pump infusion of thyrotropin-releasing hormone and vasoactive intestinal polypeptide in rats.

Pituitary prolactin (PRL) responses to 4-day continuous infusion of thyrotropin-releasing hormone (TRH) and vasoactive intestinal polypeptide (VIP) were investigated in unanesthetized male rats using Alzet osmotic minipumps. The TRH dose infused was 3.6 micrograms/day and the VIP dose was 32.8 micrograms/day. Infusion of TRH with osmotic pumps elevated the plasma PRL level compared to controls over the 4-day infusion period. However, mean levels of PRL tended to decrease during the 4-day infusion. On the other hand, continuous VIP infusion elicited a significant continuous PRL release over the 4-day infusion period. Thus, it may be said that the PRL responses to infused TRH and VIP were maintained during the 4-day infusion.

EFFECTS OF VASOACTIVE INTESTINAL POLYPEPTIDE ON THE RETICULO-OMASAL ORIFICE OF THE LAMB

Close intra-arterial infusion of vasoactive intestinal polypeptide in lambs produced a relaxation of the reticulo-omasal orifice similar to that seen during and immediately after sucking in lambs. Key words: Vasoactive intestinal polypeptide, reticulo-omasal orifice

Vasoactive intestinal polypeptide (VIP): effects in the eye and on regional blood flows.

The effect of vasoactive intestinal polypeptide (VIP) on regional blood flows was studied with labeled microspheres in albino rabbits. Intravenous injection of 500 ng VIP/kg b.w. during 100 s did not change the arterial blood pressure significantly, but caused a rise in intraocular pressure (IOP) and an increase in the choroidal blood flow by 35%, while the blood flow through the anterior uvea was unaffected. The most pronounced vasodilation was observed in the pancreas, the thyroid gland and the parotid gland. In these tissues local blood flow increased by more than 100%. Other tissues, in which this dose of VIP produced vasodilation, were the submandibular gland, the eyelids, the nictitating membrane, the choroid plexus and the heart muscle. Ganglionic or muscarinic blockade had little or no effect on the VIP-induced vasodilation in most of the tissues. Intracameral injection of VIP (1 microgram) produced vasodilation in the iris and the ciliary body, but did not affect IOP. VIP had no apparent effect on the pupil size or the blood-aqueous barrier. In experiments with direct blood flow determination from an opened vortex vein intravenous infusion of VIP, 100 ng X kg-1 X min-1 b.w., during five minutes reduced the uveal vascular resistance by about 50%. This study shows that VIP is a potent vasodilator in many tissues at doses hardly affecting the arterial blood pressure and supports the suggestion, that VIP is responsible for the non-cholinergic vasodilation in the eye caused by facial nerve stimulation.

Mechanism of the Antidiarrheal Effect of Loperamide

To determine whether the antidiarrheal effect of loperamide is due to an effect on intestinal motor function or to an acceleration of the rate of absorption by the intestine (as has been suggested recently), we studied absorption during experimental diarrhea produced by the rapid intragastric infusion of electrolyte solution. In studies in which a 2700-ml bolus of electrolyte solution was infused into the stomach over 90 min, loperamide delayed the appearance of rectal effluent in each of 5 subjects and decreased the volume of rectal effluent from 1090 +/- 118 to 770 +/- 73 ml (p = 0.05). When intragastric infusion was continued for 5 h, producing steady-state total gut perfusion, the volume of effluent produced per unit time and the concentration of a nonabsorbable polyethylene glycol marker in rectal effluent was not different with or without loperamide, indicating that loperamide did not alter the rate of absorption by intestinal mucosal cells. Loperamide also had no effect during steady-state perfusion when absorption rates were reduced by intravenous infusion of vasoactive intestinal polypeptide. Loperamide did substantially increase the intraluminal volume of the total gut, from 985 +/- 131 to 1764 +/- 195 ml (p less than 0.02). These results suggest that loperamide exerts its antidiarrheal effect by a change in the motor function of the intestine, which results in increased capacitance of the gut and a delay in the passage of fluid through the intestine. This change in motor function, rather than a change in the rate of absorption by intestinal mucosal cells, is responsible for the antidiarrheal effect of loperamide in our experimental diarrhea model.

Haemodynamics of pelvic nerve induced penile erection in the dog: possible mediation by vasoactive intestinal polypeptide.

The haemodynamics of erection were elucidated in the anaesthetized dog by analysing in quantitative terms the changes of penile arterial inflow, venous outflow and tissue volume during graded pelvic nerve stimulation. The study also provides information on possible neurotransmitter mechanisms of the erectile response. Erection evoked by pelvic nerve stimulation appeared to result from two main circulatory events: first, there was a prompt dilatation of the penile 'resistance vessels', causing a greatly increased arterial inflow which in the early phase bypassed the cavernous bodies and, hence, increased venous outflow to the same extent. Secondly, the erectile response proper began after a distinct delay (approximately equal to 20 s). This was apparently caused by sudden opening of low resistance 'shunt vessels' diverting part of the arterial inflow into the cavernous bodies, leading to rapid filling. During the filling phase arterial inflow greatly exceeded venous outflow, and returned to the venous outflow level again in the steady state of full erection. The initial dilator response seemed to ensure rapid erection by establishing a high pressure head from the arterial microvessels to the cavernous spaces. The threshold frequency for the penile vasodilator response to pelvic nerve stimulation was 1-2 Hz and was always higher for the erectile volume response, viz. 2-4 Hz. Maximal effects for both were obtained at 16 Hz, causing on the average a 25-fold increase in peak arterial inflow, a 17-fold increase in venous outflow and a 107% increase in penile volume. Muscarinic blockade by atropine caused no significant decrease in the blood flow response induced by pelvic nerve stimulation, but clearly curtailed the erectile response. This indicates that the dilatation of the penile 'resistance vessels' is mainly non-cholinergic in nature, whereas a cholinergic mechanism seems to contribute to the erectile volume response proper. Pelvic nerve stimulation caused a substantial output of vasoactive intestinal polypeptide (VIP) from the penis which was correlated in onset and duration to the vasodilator response. Intra-arterial (I.A.) infusion of VIP elicited moderate erection and a penile vasodilator response which resembled the neural response. Similar effects were evoked by I.A. infusion of substance P, but the output of this peptide from the penis during stimulation was poorly correlated to the vascular events. These in vivo observations indicate that VIP might be the neurotransmitter responsible for the non-cholinergic pelvic nerve induced penile vasodilatation.

Effect of vasoactive intestinal polypeptide infusion on cardiovascular function in man.

Effect of vasoactive intestinal polypeptide infusion on cardiovascular function in man.

Production of Secretory Diarrhea by Intravenous Infusion of Vasoactive Intestinal Polypeptide

We attempted to reproduce the diarrhea of pancreatic cholera syndrome with prolonged (10-hour) administration of vasoactive intestinal polypeptide (VIP) in five healthy nonfasting subjects. The polypeptide was given as a continuous intravenous infusion at a rate of 400 pmol per kilogram of body weight per hour. By two hours the plasma VIP concentration had risen from a normal basal value of 15.3 +/- 0.2 (mean +/- S.E.M.) to 129 +/- 40 pmol per liter--within the range found in patients with pancreatic cholera syndrome. In each subject profuse watery diarrhea developed within 4.3 +/- 0.8 hours (range, 2.0 to 6.3), and the mean stool weight at 10 hours was 2441 +/- 600 g (normal 24-hour stool weight, less than 200 to 250 g). The results of stool analysis were consistent with secretory diarrhea. Between the first and last stool, there were significant increases in fecal sodium and bicarbonate concentrations and in pH. The large fecal bicarbonate loss induced hyperchloremic metabolic acidosis, which is characteristic in patients with pancreatic cholera syndrome. Our study suggests that VIP is not merely a marker of pancreatic cholera, but is the mediator of watery diarrhea in this syndrome.

Vasoactive intestinal polypeptide and endometrial blood flow in the goat

Endometrial blood flow was measured in seven goats twice before, once during, and twice after the close intra-arterial infusion of 300 pmol/min of vasoactive intestinal polypeptide (VIP). A saline solution of 85krypton was injected intra-arterially and local blood flow calculated from the disappearance rate of the isotope from tissue surrounding a miniature Geiger-Müller probe in the uterine lumen. Initial blood flows (median and range) in animals pretreated with oestradiol-17β ( N = 4) or with a regimen of oestradiol-17β and progesterone ( N = 3), respectively, were 0.21 (0.11–0.35) and 0.20 (0.06–0.27) ml min −1 g −1. No significant change in endometrial blood flow occurred during or after the infusion of VIP, although the dose was sufficient to increase heart rate from 2.14 ± 0.15 to 2.32 ± 0.16 Hz ( P < 0.001). The results indicate that VIP, in a dose known to increase myometrial blood flow in goats, is unable to evoke vasodilatation in the endometrium of this species. Since there is a corresponding variation in the density of nerve fibers containing VIP, it is suggested that VIP may play a role in regulating the partition of uterine blood flow in goats.

Vasoactive intestinal polypeptide (VIP) increases vaginal blood flow and inhibits uterine smooth muscle activity in women.

The human vagina and uterus are heavily innervated by VIP-containing nerve fibres. In the present study, we have measured vaginal blood flow, transmucosal oxygen tension and uterine smooth muscle activity during stepwise intravenous infusion of vasoactive intestinal polypeptide (VIP) (0, 100, 300, 900 pmol kg-1 h-1) in non-pregnant women. Vaginal blood flow was measured by the heat clearance technique, transmucosal oxygen tension by an O2-electrode and uterine activity by a micro-tip pressure catheter in the uterine cavity. Arterial blood pressure, pulse frequency and the concentration of VIP in peripheral venous blood were monitored. VIP induced a concentration-dependent increase in vaginal blood flow. The transmucosal oxygen tension was not significantly changed by VIP. The maximum dose of VIP decreased systolic as well as diastolic blood pressure and increased pulse frequency. VIP inhibited uterine activity. These findings suggest that VIP participates as a neurotransmitter in the control of genital physiological responses.

The effect of vasoactive intestinal polypeptide on meal-stimulated gastric acid secretion in man.

The effect of vasoactive intestinal polypeptide (VIP) on meal-stimulated gastric acid secretion was studied in six healthy volunteers. Acid secretion was stimulated by instillation of a 10% solution of peptone, which was adjusted to pH 5.5, circulated through the stomach via a double-lumen gastric tube by a peristaltic pump. The acid secretion was estimated by continuous titration by a pH-stat. The subjects were studied twice on separate days, receiving an intravenous infusion of either VIP (1 microgram/kg/h) or saline. No effect on acid secretion was found. Mean serum gastrin concentration rose from 42 pmol/l to 150 pmol/l during meal stimulation and was unaffected by infusion of VIP. Plasma VIP concentration during infusion of saline was 6.8 pmol/l and during VIP infusion, 82.8 pmol/l. Plasma VIP concentration was unaffected by the peptone meal.

Effects of Vasoactive Intestinal Polypeptide upon Ovarian Steroids, Ovum Transport and Fertility in the Rabbit 1

The purpose of this study was to determine the effects of infused vasoactive intestinal polypeptide (VIP) upon reproductive function in the female rabbit. Intravenous infusions of VIP (37.5, 75, and 150 pmol/kg per min) induced acute dose-dependent increases in plasma progesterone (P) but not estradiol (E2) or testosterone (T) in estrous rabbits. This P effect was not associated with an increase in plasma prolactin (Prl) and was not altered by pretreatment with a Prl-inhibiting regimen of bromocriptine. In rabbits stimulated to ovulate with 75 IU human chorionic gonadotropin (hCG) and coitus, plasma P and E2 increased, reaching a peak at 180 min following stimulation. VIP (75 pmol/kg per min) infused from 120 to 180 min following the ovulatory stimuli increased this P peak but did not effect E2 levels. This VIP infusion had no effect upon fertility or upon the number of corpora lutea, uterine implants, or viable conceptuses. Infusions of VIP for 60 min at the P peak, and for 240 min at the time of ovulation, had no significant effect upon ovum pickup or the rate of ovum transport. These observations suggest that 1) VIP infusions in rabbits can increase plasma P from both the basal levels of estrus and from the peak levels preceding ovluation. 2) Infusions of VIP at the time of the preovulatory steroid surge or during ovulation have little effect upon fertility or gamete transport in the rabbit. 3) Endogenous VIP may play a role in the regulation of P secretion in the rabbit.

Effect of vasoactive intestinal polypeptide on uterine blood flow in pregnant ewes

Vasoactive intestinal polypeptide has been localized in the uterine vasculature, uterine smooth muscle and the placenta of several species. Vasoactive intestinal polypeptide is a potent uterine vasodilator in nonpregnant sheep and also abolishes spontaneous uterine contractile activity, but the effects of this polypeptide on the uterine vasculature of the pregnant animal is currently unknown. The present experiments were performed in seven late-term pregnant sheep which were chronically catheterized to evaluate the uterine vascular effects of vasoactive intestinal polypeptide. An intra-arterial catheter was placed in a branch of the main uterine artery to allow administration of vasoactive intestinal polypeptide directly into the uterine vasculature. Uterine blood flow was continuously monitored via an electromagnetic flow transducer on both main uterine arteries. Vasoactive intestinal polypeptide infused at the rate of 1 to 30 μg/min produced dose-related reductions in uterine blood flow (33% ± 9% at 30 μg/min). This decrease was due to a reduction in systemic arterial blood pressure, since calculated resistance in the uterine vasculature that received the vasoactive intestinal polypeptide did not change significantly. In addition, the contralateral uterine vasculature that did not receive direct intra-arterial infusions of vasoactive intestinal polypeptide showed identical changes. These data suggest that vasoactive intestinal polypeptide produces peripheral vasodilation at doses which have very little uterine effect locally. These data can be interpreted to mean either that high local endogenous production of vasoactive intestinal polypeptide prevents exogenously administered vasoactive intestinal polypeptide from exerting its vascular effects, or that vasoactive intestinal polypeptide is a very weak uterine vasodilator in prognant ewes. The clarification of these possibilities will require further experimentation.

Studies of the mechanism of the antidiarrheal effect of codeine.

To determine whether the antidiarrheal action of opiate drugs in humans is due to enhanced intestinal absorption rates, as suggested by recent experiments in animals, or is due to altered intestinal motility, as traditionally thought, we studied the effect of therapeutic doses of codeine on experimental diarrhea and on the rate of intestinal absorption of water and electrolytes in normal human subjects. Our results show that codeine (30-60 mg i.m.) markedly reduced stool volume during experimental diarrhea induced by rapid intragastric infusion of a balanced electrolyte solution. There was, however, no evidence that codeine stimulated the rate of intestinal absorption in the gut as a whole or in any segment of the gastrointestinal tract, either in the basal state or when absorption rates were reduced by intravenous infusion of vasoactive intestinal polypeptide. We also measured segmental transit times to determine whether and where codeine delayed the passage of fluid through the intestine. Codeine caused a marked slowing of fluid movement through the jejunum, but had no effect on the movement of fluid through the ileum or colon. In other studies, we found that the opiate antagonist naloxone did not significantly affect water or electrolyte absorption rates in the jejunum or ileum. We conclude (a) that therapeutic doses of codeine increase net intestinal absorption (and thereby reduce stool volume) by increasing the contact time of luminal fluid with mucosal cells, not by increasing the rate of absorption by the mucosal cells; and (b) that endogenous opiates do not regulate intestinal absorption in humans.

Effect of vasoactive intestinal polypeptide (VIP) on the in vitro and in vivo motility of the rabbit reproductive tract

Isolated segments of rabbit ampulla and isthmus and strips of uterus and cervix were spontaneously mechanically active in vitro, and this activity was inhibited in a dose-dependent manner by 2 to 200 ng/ml vasoactive intestinal polypeptide (VIP). The oviductal segments were the most inhibited, the uterine strips the least inhibited. These tissues were stimulated to contract in a dose-dependent manner by epinephrine (EPI), with the uterus and cervix being the more responsive. VIP (200 ng/ml) produced only a slight noncompetitive antagonism of this stimulation. Recordings made with miniature force transducers showed the isthmus, uterus, and cervix also to be spontaneously active in vivo. This activity was inhibited by injections (1, 10, and 20 micrograms) and infusions (1.0 and 2.5 micrograms/min) of VIP. The isthmus was the most inhibited, the cervix the least inhibited. Possible physiologic implications of these pharmacologic effects are discussed.